As cells age they accumulate insoluble protein aggregates. This is observed in cell types ranging from bacteria to human neurons, and is emphasized in a number of human neurodegenerative diseases. While the aggregation of certain proteins and their associated proteotoxicity has been linked to specific diseases, the dysregulation of protein homeostasis that occurs with normal aging can cause the accumulation and aggregation of a wide range of proteins, that are not associated with a human disease per se. Aging is also associated with increased levels of pro-inflammatory (Pro-I) molecules, both systemically and in the brain. As with proteotoxicity, aging-associated chronic inflammation presents risk for cognitive impairments and neurodegenerative diseases. While an extensive body of literature links disease-associated proteotoxicity with neuronal cell death, much less is known about the functional relationship between overall intracellular protein aggregation and inflammation in the aging central nervous system. In addition, there are likely synergistic interactions between age-associated protein aggregation, disease-associated proteotoxicity, and systemic inflammation. The hypothesis is that normal aging results in the ubiquitous accumulation of protein aggregates, and that these aggregates induce an inflammatory response within neurons that enhances the probability of neurodegenerative disease. Furthermore, this 'background' inflammation acts synergistically with disease-specific proteins (e.g., amyloid beta) as well as other Pro-I molecules to promote brain pathology. The Aims of this application test this hypothesis. Insoluble, ubiquitinated, and glycated proteins accumulate in the fly, mouse, and human brain with age. A candidate Alzheimer's disease (AD) drug reduces the abundance of a subset of these proteins and extends life span in mice and flies. This drug candidate also reduces neuroinflammation in mice. The goal of Aim 1 is to identify and characterize the full range of proteins that aggregate and accumulate as a function of aging in the brains of rapidly aging mice, mouse models of AD, and human patients with AD. Proteins identified in Aim 1 will be used in Aim 2 to determine the extent to which these aggregating proteins potentiate inflammation, either in conjunction with extracellular Pro-I molecules, or by interacting with the disease-associated proteins A? or huntingtin. To determine the mechanisms involved experiments will focus on the interaction between protein aggregates and pattern recognition receptors that are known to bind to conformationally constrained proteins (such as aggregates), resulting in inflammasome activation. In Aim 3, proteins identified in Aim 1 and characterized in Aim 2 will be over expressed in rapidly aging SAMP8 mice and in an AD transgenic mouse model. Effects on memory, glial and microvascular inflammation and brain pathology will be assessed. Together, these data will clarify the mechanistic link between aging-associated protein aggregation and inflammation, leading to ?a better understanding of AD in the context of aging? as required for this PAR.